Preferential expression of antioxidant response element mediated gene expression in astrocytes.

Abstract

Transcriptional control of target genes by antioxidant/electrophile response elements has been well described in peripheral tissues. Genes that are regulated by this mechanism include the antioxidant enzymes NAD(P)H:quinone oxidoreductase, gamma-glutamyl cystine synthetase and glutathione-S-transferase. Antioxidant/electrophile response elements within a gene's promoter confer induction by low-molecular-weight electrophilic compounds such as tert-butylhydroquinone and dimethyl fumarate. We have now examined the ability of antioxidant/electrophile response elements to elicit gene expression in neurons and astrocytes in both brain slices and primary cultures using transient transfection of promoter reporter constructs. Our results using a heat-stable human placental alkaline phosphatase reporter indicate that antioxidant/electrophile response element mediated gene expression is largely restricted to astrocyte cell populations. Placental alkaline phosphatase expression was significantly elevated in astrocytes treated with the antioxidant/electrophile response element inducer dimethyl fumarate. Mutant constructs lacking a functional antioxidant/electrophile response element abolished all placental alkaline phosphatase expression in astrocytes. We suggest that astrocytic metabolic processes that normally aid and/or protect neurons may be controlled via this inducible system.